The present invention relates to a novel medicinal use of 5-HT3 receptor antagonists, in particular cilansetron, or their pharmacologically compatible derivatives, such as salts and/or solvates, for the treatment and/or inhibition of non-digestive tract derived abdominal disorders associated with pain, in particular interstitial cystitis, chronic pelvic pain syndrome and/or abdominal pain associated with endometriosis.
Regarding the therapeutic potential of 5-HT3 receptor antagonists, it is already widely known that those can play a beneficial role in i.a. the treatment of gastrointestinal disorders (see e.g. Z. H. Israili, Curr. Med. Chem.—CNS Agents 1 (2001) 171-199 for a review).
The use of 5-HT3 receptor antagonists for the treatment of urinary incontinence is already known from European patent publication no. EP 467,365.
Johansen et al. (see Current Opinion in Urology, 12/1 (2002) 63-67, cited as “Johansen et al.” hereinafter) discuss a relation between the possible aetiological role of mast cells in interstitial cystitis and the importance of serotonin as a therapeutic agent in interstitial cystitis and chronic pelvic pain syndrome.
Of non-digestive tract derived abdominal disorders associated with pain, interstital cystitis, chronic pelvic pain syndrome and abdominal pain associated with endometriosis may best be cured by administration of 5-HT3 receptor antagonists. Therapy of Interstitial Cystitis is preferred. According to the invention, “therapy” is meant to comprise either inhibition and/or treatment of a disorder.
Interstitial cystitis is a chronic disorder of the urinary bladder characterized by symptoms of urinary frequency and urgency, suprapubic pain, dyspareunia (anticipation of pain during sexual intercourse), nocturia and chronic pelvic pain (see e.g. G. Newsome, Journal of the American Academy of Nurse Practitioners, 15(2) (2003) 64-71). Interstitial cystitis occurs primarily in women, but also in men. Several pathophysiological mechanisms have been proposed in the past few years including epithelial dysfunction, activation of mast cells, neurogenic inflammation, autoimmunity, occult (viral or bacterial) infection, toxin exposure and pelvic floor dysfunction. Onset of interstitial cystitis is predominately in adulthood, although it does occur in childhood. The prevalence of interstitial cystitis has ranged from about 8 to about 60 cases per 100,000 female patients, depending on the population evaluated. About 10% of patients have severe symptoms that are associated with Hunner's ulcers on bladder biopsy. The rest could be grouped in those with or without bladder inflammation.
Interstitial cystitis in men is probably underdiagnosed and is most commonly misdiagnosed as prostatitis. Symptoms of Interstitial Cystitis are exacerbated by stress, certain foods and ovulatory hormones. Many patients also experience allergies, irritable bowel syndrome (IBS) and migraines. There have been various reports indicating dysfunction of the bladder glycosaminoglycan (GAG) protective layer and many publications showing a high number of activated bladder mast cells.
Diagnosis is by history, physical examination, laboratory tests, and cystoscopic examination. It thus largely remains a diagnosis of exclusion. Approved treatments to date include intravesical administration of dimethylsulfoxide (DMSO) or oral pentosanpolysulfate (PPS), but today's management of Interstitial Cystitis also may include dietary changes, antihistamines, tricyclic antidepressants, oral and intravesicle glucosaminoglycans, hydrodistention, pain management and emotional support. Criteria for diagnosis of interstitial cystitis have been established by the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (Gillenwater et al. J. Urol 140 (1988) 203-208). These include glomerulations or Hunner's ulcer on cystoscopic examination and pain associated with bladder or urinary urgency. Recently, interstitial cystitis has frequently been divided into two subtypes: classical and nonulcer disease (Peeker and Fall, J. Urol. 167 (2002) 2470-2472).
Chronic pelvic pain syndrome is a syndrome often related to interstitial cystitis. According to the classification of the U.S. National Institiute of Health as “Type III Prostatitis” (see J. N. Krieger et al., JAMA 282 (1999) 236-237), it is regarded as a chronic, abacterial prostatitis. Patients with non-inflammatory chronic pelvic pain syndrome are the largest group of prostatitis patients according to the U.S. National Institute of Diabetes and Digestive and Kidney Diseases classification and are characterized by the absence of objective findings. Interestingly, for the majority of patients, no objective findings link the symptoms of prostatitis to the prostate gland or to the male genital tract. Thus, no findings seem to link the symptoms of chronic pelvic pain syndrome to the male in particular. Mounting evidence instead suggests that a significant overlap may exist between interstitial cystitis and chronic pelvic pain syndrome in epidemiology, pathophysiology and even therapy. In fact, both conditions might represent different manifestations of the same disease process. For example, very similar theories of pathogenesis exist for both conditions. Occult infections, epithelial dysfunction, neurogenic inflammation mast cell activation and autoimmunity are features that seem to play a role in the formation of interstital cystitis as well as in the formation of chronic pelvic pain syndrome (see e.g. Johansen et al.; R. M. Moldwin, Current Urology Reports 3/4 (2002) 313-318). Similar medications for both conditions will therefore seem promising. For a review on chronic pelvic pain syndrome see, for example, M. McNaughton-Collins et al., Ann. Intern. Med. 133 (2000) 367-381.
Endometriosis is a well-known gynecological disorder that affects 10 to 15% of women of reproductive age. It is a benign disease defined as the presence of viable uterine tissue, e.g. endometrial gland and stroma cells, outside the uterine cavity. It is most frequently found in the pelvic area, in particular in the ovaries. In women developing endometriosis, the endometrial cells entering the peritoneal cavity by retrograde menstruation (the most likely mechanism) have the capacity to adhere to and invade the peritoneal lining, and are then able to implant and grow. The implants respond to steroid hormones of the menstrual cycle in a way similar to the endometrium in the uterus. The infiltrating lesions and the blood from these lesions, which are unable to leave the body, cause inflammation of the surrounding tissue. The most common symptoms of endometriosis are dysmenorrhoea, dyspareunia and (chronic) abdominal pain. The occurrence of these symptoms is not related to the extent of the lesions. Some women with severe endometriosis are asymptomatic, while women with mild endometriosis may have severe pain. To date, no reliable and easy to use non-invasive test is available to diagnose endometriosis. Laparoscopy has to be performed to diagnose the disease. Endometriosis is classified according to the four stages established by the American Fertility Society (AFS). Stage I corresponds to minimal disease, while stage IV is severe, depending on the location and the extent of the endometriosis. Endometriosis is found in up to 50% of women with infertility. However, currently no causal relation has been proven between mild endometriosis and infertility. Moderate to severe endometriosis can cause tubal damage and adhesions leading to infertility. Despite extensive research, the cause of endometriosis is still largely unknown. Several theories for the origin of endometriosis have been proposed, although no single hypothesis explains all cases of the disease completely. However, the key event in all of these theories seems to be the occurrence of retrograde menstruation. The aims of treatment of endometriosis are currently pain relief, resolution of the endometriotic tissue, and restoration of fertility (if desired). The two common treatments are surgery or anti-inflammatory and/or hormonal therapy or a combination thereof.